Recent clinical studies have clearly shown that lowering serum cholesterol levels reduces the incidence of coronary artery disease, the leading cause of death in the United States. Using the oxylanosterol mimic, DMP 565, the feasibility of targeting RNA/protein interactions as a method for developing improved therapeutics has been demonstrated. The overall goal of the project is to exploit this technology for the development of more efficacious or less expensive cholesterol-lowering drugs. These compounds could be used alone or in combination with current therapies to reduce the need for expensive hospitalizations and surgeries for the CAD patient. Identification of a lead compound will be achieved through the following specific aims: map the putative HMGR 5'-UTR cis- element and synthesize a library of compounds targeted to the RNA structure; screen libraries to identify compounds that modulate the 5'- UTR/protein interaction; test active compounds in cell-based assays and in animal models; and determine the toxicity of the active compounds. It is anticipated that upon completion of this proposal a lead compound will have been identified which will be developed further in Phase III leading to ArnaX filing an IND and conducting a Phase I/ll clinical trial. PROPOSED COMMERCIAL APPLICATIONS: The potential commercial application of the research proposed in this grant is the development of an improved hypocholesterolemic drug which has a different mechanism of activity from the currently available drugs. These compounds may have an improved spectrum of action, be more efficacious or be less expensive. Such a drug could then be used alone or in combination with the current panel of drugs.